19-nor-10alpha-pregnene and delta1(10)-19-nor-5alpha-pregnene compounds



I fertility -control.

United States Patent 3,248,390 l9-NOR-10a-PREGNENE AND A -19-N0R.Sa-PREGNENE COMPOUNDS Albert Bowers and Otto Halpern, Mexico City,Mexico,

assignors to Syntex Corporation, Panama, Panama, a corporation of PanamaNo Drawing. Filed Oct. 10, 1963, Ser. No. 315,349 24 Claims. (Cl.260-23955) The present invention rel-ates to novelcyclopentanophenanthrene derivatives and to a process for the productionthereof.

More particularly the present invention relates to novel19-nor-10m-pregnene and A -19-nor-5a-pregnene compounds.

The novel compounds of the present invention may be represented by thefollowing formulae:

In the above formulae, R represents hydrogen or a hydrocarbon carboxylicacyl group of less than 12 carbon atoms; R represents hydrogen,hydroxyl, or a hydro- ...0 lower alkyl ...0 lower alkyl at the16a,17a-position.

The acyl and acyloxy groups are derived from hydrocarbon carboxylicacids containing less than 12 carbon atoms which may be saturated orunsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, oraromatic, and may be substituted by functional groups such as hydroxy,alkoXy containing up to 5 carbon atoms, acyloxy containing up to 12carbon atoms, nitro, amino or halogen. Typical ester groups are theacetate, propionate, enanthate, benzoate, trimethylacetate,t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, andfi-chloropropionate.

The compounds represented by the above formulae are powerfulprogestational agents with good oral activity. In addition they haveanti-androgenic, anti-gonadotrophic and anti-estrogenic properties andare very useful in Furthermore, they may be used in the treatment ofpremenstrual tension and exhibit blood cholesterol lowering and diureticactivities.

The novel compounds of the present invention are prepared by the processexemplified as follows:

.Serial No. 293,831, filed July 9, 1963, from the corresponding6-hydroxy-A -compound by dehydration in the presence of an acid, e.g.,acetic acid, at C. for approximately 1 hour. The 6-hydroxy-A -cornpoundmay, in turn, be produced from the corresponding 6- ketone byconventional reduction.

In practicing the process outlined above, the starting A-19-nor-pregnadien-3fl-ol-2O-one derivative (I) is treated with hydrogenin the presence of a suitable catalyst such as palladium in a number offorms, for example 5% palladium on calcium carbonate, 5% palladium oncharcoal, etc., in a suitable organic solvent, preferably a loweralkanol such as methanol, until the absorption ceases, thus affording aproduct which upon conventional chromatography gives, surprisingly, apredominant amount of the corresponding A -19-n0r-10a-pregnen-3/3-ol-20-one (II) and, in rnuch smaller quantities, the corresponding A-19-nor-5a-pregnen-3fl-ol-2O-one derivative (III). Upon treatment of theA -19-nor-10a-pregnen-3fl-ol-20-one componds (II) under conventionalOppenauer conditions there are producedrthe corresponding novel A-l9-nor-10a-pregnene-3,2O-dione derivatives (IV).

The compounds of the present invention having a secondary hydroxyl groupare conventionally acylated in pyridine with an acylating agent, such asan anhydride or a chloride of a hydrocarbon carboxylic acid of the typedescribed hereinbefore, to give the corresponding acylates.

The compounds of the present invention having in the molecule a tertiaryhydroxyl group, i.e., at C-17, are conventionally esterified in thepresence of p-toluenesul- 'fonic acid with an acylating agent, such asacetic anhydride, caproic anhydride, cyclopentylpropionic anhydride,

3 or enanthic anhydride, to produce the corresponding esters.

The hydrogenation step of the above process when applied to compounds ofthe androstane series, e.g.,

' 4 Example Ill The compounds Nos. 3 to 12, inclusive, were treatedaccording to Example II, thus giving respectively:

water 10% sodium carbonate solution and water until neutral, dried overanhydrous sodium sulfate and evaporated to dryness. Crystallization fromacetone-hexane afforded A -l9-nor-l0a-pregnene-3,20-dione (Cpd. No. 13).

Upon treatment of compound No. 2 by the same procedure there wasproduced A -l9-nor-5a-pregnene-3,20-dione (Cpd. No. 14).

A -l9-nor-androstadiene-3fl-ol-l7-one, etc., yields sim- 5 Cpd N ilarlya predominant amount of the corresponding A 19- '1'6a methy1 A4 19 norlowpregnenesmdione, nor-lOa-androstene derivatives and the corresponding16 16fl methy1 A4 19 nOr 10a pregnene 3 zodione,1(10)-19-nor-5x-androstene compounds in smaller yield, 16a17uisopmpylidgnedioxy which is in accordance with our copending US. Patentpregnene3 20 diOne application Serial No. 315,390, filed of even datenow 18 A4 19 nOr iowpregngmwwomzodione abandoned. The process therefore,is a general method 1 16a methyl A4 for producing predominantly A-19-nor-10a-steroids of the 3 20 dione androstane and pregnane seriesfrom the corresponding 20 i A1 19 n0r 5a pregnene 3 2o dione, A -dienes.21 1 h 1 1 yl-A -l9-nor-5a-pregnene-3,20-d1one The followrng g ificeirlamples sevehto rllustrate but 22 16a17a isopmpylidenedioxy A1 arenot intended to limit t e scope o t e present rnvenpregnenesimdione 23.A -19-nor-5a-pregnen-17a-ol-3,20-dione,

Example I 24. g6zao-dr nethyl A 19 nor 5u-pregnen-l7a-ol- 10116. Asuspension of 0.5 g. of 5% palladium on charcoal E l 1V ca-talyst m 50of methanl h lhgY f f Q A mixture of 1 g. of compound No. l, 4 cc. ofpyridine nunutes. A solution of 2 g. of A 19 nor pregnadren and 2 cc. ofacetlc anhydrrde was kept at room temper- 3fi-ol-20-one (obtalned 1naccordance W1th our copendmg r ature overnight, poured into ice water,the formed prec1p1- US. patent applrcatlon Ser1al No. 293,831, [filedJuly 9, 2,

tate was filtered washed with water and dried. Crystal- 1963) 1n 200 cc.of methanol was added to the catalyst fm actone hexane ave Ailgmoplow renew and stirred under a hydrogen atmosphere until the uptake 12 Ion m Ig p g of hydrogen ceased. After removal of the catalyst by 31 i g i ggifg were treated b filtration the solution was evaporated and the crudeth g i fur fi res eotivel y residue was chromatographed on alumina andthe solid e We proce u us In p fractions purified by crystallizationfrom methylene chlo- Cpd. No.:

- ride-hexane, thus giving predominantly A -l9-nor-l0a- 26. A)-19-nor-5a-pre gnen-3fi-ol-20-one acetate,

pregnen-S/i-ol-ZO-one (Cpd. No. 1) in a much smaller 27. 16a methyl A l9nor-10a-pregnen-3 3-olamount A 19 DOf-Socregnen-3 -o*l-20-one (C d.20-one acetate,

No. 2). 35 28. 16 8 methyl A 19 nor 10a pregnen-3fi-ol- The startingcompounds listed hereinafter under A, 20-one acetate, obtained inaccordance with our aforesaid application were 29. l6a,l7aisopropylidenedioxy A l9-nor-l0atreated according to the aboveprocedure, thus yielding pregnen-3fl-ol-20-one acetate, redominantly thecorresponding compounds set forth 30. A 19 nor 1004 pregnene-3,17a-diol-20-one P under B and in small amounts those disclosed under C:3-acetate,

A Opd. B Cpd. C No. No.

A1 I -19 r-pregnadieu-3B-ol- 19-nor-10 a-pregnen-3B-ol-20-one. A-19-n0r-5 a-pregncn-3B-ol-20- dicnc 3 8,17 a-diOl-lO-ODG. 35,17a-dlOl-ZO-OHO. 36,17wdi0l-20-0ne.

Example 11 31. 16a methyl A l9 nor-10a-p1'egnene-3/3,17a-

diol-20-one 3-acetate,

diol-20-one S-acetate.

Example V The starting compounds of Example IV were treated followingexactly the procedure described in that example except that aceticanhydride was substituted by caproic anhydride, propionic anhydride,enanthic anhydride and cyclopentylpropionic anhydride thus affordingCpd. No.:

respectively the wrresponding caproates, propionates,

enanthates and cyclopentylpropionates of said starting compounds.

Example VI To a solution of 5 g. of compound No. 6 in 100 cc. ofanhydrous benzene there were added 1 g. of p-toluenesulfonic acid andcc. of caproic anhydride and the mixture was allowed to stand for 24hours at room temperature, poured into ice and water, and the resultingmixture stirred to effect hydrolysis of the excess anhydride. Thebenzene layer was separated and washed with 10% sodium carbonatesolution and water. Drying, evaporation and crystallization of theresidue from ether-hexane produced A -l9-nor-10a-pregnene-33,l7a-diol-20-one dicaproate (Cpd. No. 37).

The compounds Nos. 7, l1, 12, 18, 19, 23 and 24 were treated inaccordance with the latter procedure, thus yielding respectively:

3 8. l 6oc-lmethyl-lA 19-nor-1 Oa-pregnene-B 13, l7a-diol- ZO-onedicaproate.

A -19-nor-5a-pregnene-3/3,17a-diol-20-one dicaproate.

diol-ZO-one dicaproate.

41. A -19-nor-10a-pregnend7u-ol-3,ZO-dione caproate.

42. 16a-methyl-A -l9-nor-l0a pregnen-17u-ol-3,20-

dione caproate.

43. A -19-nor-5u-pregnen-17a-ol-3,2O dione caproate.

44. l6a-methyl-A -19-nor-5m pregnen-17a-ol-3,20-

dione caproate.

Example VII The starting compounds of Example VI were treated followingexactly the procedure described in that example, except that caproicanhydride was substituted by acetic anhydride, propionic anhydride,enanthic anhydride and cyclopentylpropionic anhydride thus afiordingrespectively the corresponding acetates, propionates, enanthates, andcyclopentylpr-opionates of said starting compounds.

We claim:

1. A compound of the following formula:

wherein R is a member of the group consisting of hy-' drogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R isselected from the group consisting of hydrogen, hydroxyl and ahydrocarbon. carboxylic acyloxy group of less than 12 carbon atoms; T isa member of the group consisting of hydrogen, amethyl and ,B-methyl; andR and T together form the group ...0 lower alkyl ...O lower alkyl at the16a,l7a-position.

2. A -19-nor-5a-pregnen-3fi-ol-20-one. 3. 16a-methylA-19-nor-5a-pregnen-3 3-ol-20 one. 4. l6B-methyl-A-l9-nor-5ot-pregnen-3B-ol-ZO-one. 5. 16al7a-isopropylidenedioxy A-l9-nor-5a-preg- 4 nen-3/8-ol-20-one.

6. A -19-nor-5 a-pregnene-3 13,17ot-dl0l-20-0I1B.

l6a-methyl-A -19-nor Sa-PICgIlCIlB 35,170:-

- 6 7. 16a-methyl-A -19-nor-5 pregnene-3fi,l7a-diol- 20one.

8. A compound of the following formula:

wherein R is a member of the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R isselected from the group consisting of hydrogen hydroxyl and ahydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T isa member of the group consisting of hydrogen, amethyl and fi-methyl; andR and T together form the group 0 lower alkyl 0 lower alkyl at thel6a,l7u-position.

12. 16a,l7u-isopropylidenedioxy-A -19 nor-10a-pregnen-3fi-ol-20-one.

13. A -19-nor-l0a-pregnene-3/8,17a-diol-20-one.

14. 16a-methyl-A -l9-nor-l0a-pregnene 3B,17a-di0l ZO-one.

15. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen hydroxyl anda hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; Tis a member of the group consisting of hydrogen, a-methyl and ,B-methyl;and R and T together form the group ...0 lower alkyl ...0 lower alkyl 78 24. The process of claim 22 wherein the organic solvent Chen:Tetrahedron, vol. 3, pp. 43-48 (1958). is a lower alkanol. Ellis et al.:Chem. Abs., 56, col. 4813(a) (1962) References Cited by the Examinerpulglerg egai z Steroids, 1959, pp. 563 and 595, Relnhold UNITED STATESPATENT 5 Loewenthal: Tetrahedron, vol. 6, No. 4, .pp. 269-303 3,013,94512/1961 Ilavsky et a1. 19s 51 3,019,219 1/1962 Cantrall et a1. 260-23955g F k g 2 gi 6 i =g;- i g ugg1en: em. 5., co 1 OTHER REFERENCES Struckat 211.1 J. Org. Chem, 26, pp. 3883-7 (1961). Applezweig Steroid Drugs,pp. 598 \and 728, 1962, 10 McGraw-Hill, N.Y. RM-799-A6. LEWIS T PrimaryExaminer- Banton et al.: J. Chem. 800., pp. 662-31 (1962).

1. A COMPOUND OF THE FOLLOWING FORMULA: